1. Field of Invention
This invention relates generally to drug therapy in the treatment of autoimmune diseases, and more particularly to the treatment of rheumatoid arthritis by the combined synergistic action of different gold compounds.
2. Status of Prior Art
Leucocytes, a type of white cell or corpuscle found in human blood is capable of ingesting disease-producing bacteria found in the body. These defenders against infection are known as phagocytes or eating cells, and the ingestive process as phagocytosis. Phagocytes are the body's first line of defense against invading microorganisms.
An antigen is any substance which when introduced into the body induces an immune response leading to acquired immunity. The immune response results in the formation of specific antibodies. These circulate in the bloodstream to develop humoral immunity or act to increase the number of reactive cells, called lymphocytes, to develop cell-mediated immunity, or both.
The concern of the present invention is with autoimmune diseases in which antibodies are produced against an individual's own tissues by reason of some malfunction of the immune system. The immune system, in addition to defending the body against infectious agents, also promotes homeostasis, that is the maintenance of normal conditions, as by removing damaged cellular elements and by supporting immunological self-tolerance. When the mechanism of self-tolerance breaks down, various disease states may subsequently occur such as rheumatoid arthritis (RA), hemolytic anemia and other autoimmune diseases.
In joints chronically affected by RA, the normally delicate synovial membrane develops many villous folds and thickens as a result of increased numbers of synovial lining cells and the colonization of lymphocytes and plasma cells. The colonizing cells which are initially perivenular, later form lymphoid follicles having germinal centers, synthesize rheumatoid factors and other immunoglobulins.
The use of water-soluble gold compounds, such as gold sodium thiomalate or thiosulphate, against active joint inflammation is well known. The usual procedure is to inject the patient at weekly intervals with a 10 mg. dose the first week, 25 mg. the second and 50 mg. thereafter at weekly intervals until a total of 1 Gm. has been delivered or a significant improvement becomes apparent. Hydroxychloroquine is known to occasionally control symptoms of mildly active RA.
Excessive production of superoxide radicals (O.sub.2.sup.-) and lysosomal enzymes by inflammation mediator cells like polymorphonuclear leukocytes, macrophages, and platelets gives rise to a sustaining chain of events leading to tissue injury. Defense mechanisms involve a highly complex cascade of reactions with the participation of endogenous inhibitors of inflammation like superoxide dismutases, antiproteases like alpha.sub.1 -antitrypsin, alpha.sub.2 -macroglobulin and antioxidants or free radical scavengers like ceruplasmin. (See: Weissman, G et al; Leucocytes as Secretory Organs of Inflammation., Advances in Inflammation Research, 1:95-112, 1979. Edited by G. Weissman et al., Raven Press, New York, 1979).
Oxidative damage by free radicals on circulating human gamma globulin (IgG) induces IgG aggregation with all the pathophysiological properties of immune-complexes present in the plasma and synovial fluid of patients with rheumatoid arthritis. (See: Jasin, H.; Generation of IgG Aggregates by the Myeloperoxidase-hydrogen-peroxide System, The Journal of Immunology, 130: 1918-1923, 1983).
The phagocytosis of such complexes may perpetuate the production and damaging effects of lysosomal enzymes and oxygen radicals. Superoxide radicals or free radicals are products of many biological reactions of living organisms with oxygen. The survival of aerobic organisms in an oxygen environment entails a complex interplay between the products of oxygen consumption by living cells and the ability of the organism to control 0.sub.2 metabolites. Oxygen consumption results in the formation of free radicals O.sub.2.sup.- (Superoxide anion radical), H.sub.2 O.sub.2 (hydrogen peroxide) and OH (hydroxyl radical). (See: Free Radicals in Medicine and Biology. Acta Physiologica Scandinavica Symposium Upsala, 1980).
Therapeutic interference with these mediators constitutes one of the properties found desirable in so called "disease modifying agents" or "slow acting antirheumatic drugs". Auranofin (AF) an oral chrysotherapeutic agent effective in the treatment of rheumatoid arthritis, is characterized, as are the injectable gold compounds, as a slow acting drug for the control of rheumatoid inflammatory response. (See: Finkelstein, A. E. et al.; Auranofin New Oral Gold Compound for Treatment of Rheumatoid Arthritis, Ann. Rehum. Diseases, 35: 251-257, 1976; Blodget, Jr., C. R., Hener, A. M., and Pietrusko, G. R., Auranofin: A Unique Oral Chrysotherapeutic Agent, Seminar in Arthritis and Rheumatism, 12:255-273, 1984).
While AF produces a significant dose-dependent inhibition of lysosomal enzyme release and super-oxide generation during immune-complex phagocytosis, we have found in previous studies that gold sodium thiosulphate (GTS), an injectable gold compound, is ineffective at therapeutic blood gold levels. (See: Finkelstein et al., Effect of Auranofin a New Antiarthritic Agent on Immune Complex Induced Release of Lysosomal Enzymes from Human Leucocytes, Inflammation, 2: 143-50, 1977; Finkelstein et al.; Auranofin and Lysosomal Enzymes, J. Rheumatology 9 (Suppl. 8), 46-53, 1982; Roisman, F., D. Walz and A. E. Finkelstein; Superoxide Radical Production by Human Leucocytes Exposed to Immune Complexes, Inflammation, 7: 355-362, 1983).